N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study

Introduction N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD. Methods A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (COEXH) (secondary outcome), and quit rates as defined by COEXH<6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses. Results NAC treatment significantly reduced the daily number of cigarettes used (Δ mean±SD = -10.9 ± 7.9 in the NAC-treated versus -3.2 ± 6.1 in the placebo group) and COEXH (Δ mean± SD = -10.4 ± 8.6 ppm in the NAC-treated versus -1.5 ± 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by COEXH<6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder. Conclusions These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD.

A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes.

Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes.

Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents

Background Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians. Objective To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents. Design, setting, and participants We report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide. Outcome measurements and statistical analysis Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy. Results and limitations The post-endocrine-therapy patients received abiraterone (n = 32), sequential abiraterone and enzalutamide (n = 5) or enzalutamide (n = 4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1-10 cycles) were delivered, with ≥50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n = 18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis. Conclusions This is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting. Patient summary We looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments. © 2013 European Association of Urology.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

Duration of obesity and incident hypertension in adults from the Framingham Heart Study

Background: Previous studies exploring the association between obesity and hypertension generally used a single baseline measurement of obesity. The effect of accumulating excess adiposity over time on the risk of hypertension is uncertain. This study aimed to examine the relationship between duration of obesity and incident hypertension using the Framingham Heart Study.

Methods: Two thousand, nine hundred and fifty-three participants aged 30–62 years without baseline hypertension were included. Blood pressure, height and weight were measured biennially. Duration of obesity was calculated. Time to incident hypertension was analysed using time-varying Cox proportional hazards regression with age as the time scale and censoring at time of death or end of follow-up.

Results: Eighty percent of participants developed hypertension (median follow-up 15.9 years). A positive association between obesity duration and incident hypertension was observed in women. There was no longer an association when time-varying BMI was adjusted for (hazard ratio 0.95; (95% confidence interval 0.85–1.05)).

Conclusion: These findings suggest that the mechanism by which excess adiposity may increase blood pressure is primarily immediate and that long-term exposure to obesity does not further increase the risk of developing hypertension beyond the level of BMI attained.

Future directions for pharmacotherapies for treatment-resistant bipolar disorder

Current pharmacological treatments for bipolar disorder (BD) are limited and efficacy has historically been discovered through serendipity. There is now scope for new drug development, focused on the underlying biology of BD that is not targeted by current therapies. The need for novel treatments is urgent when considering treatment resistant BD, where current therapies have failed. While established drugs targeting the monoamine systems continue to be worthwhile, new biological targets including inflammatory and oxidative an nitrosative pathways, apoptotic and neurotrophic pathways, mitochondrial pathways, the N-methyl-Daspartate (NMDA)-receptor complex, the purinergic system, neuropeptide system, cholinergic system and melatonin pathways are all being identified as potential anchors for the discovery of new agents. Many agents are experimental and efficacy data is limited, however further investigation may provide a new line for drug discovery, previously stalled by lack of corporate interest.

Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats

Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1α levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction.

Implementation of the diabetes and hypertension guideline lifestyle recommendations in urban Mongolia: A qualitative study of primary care providers

Abstract
Background: Hypertension and diabetes, key risk factors for cardiovascular disease, are significant health problems globally. As cardiovascular disease is one of the leading causes of mortality in Mongolia since 2000, clinical guidelines on arterial hypertension and diabetes were developed and implemented in 2011. This paper explores the barriers and enablers influencing the implementation of these guidelines in the primary care setting.
Methods: A phenomenological qualitative study with semi-structured interviews was conducted to explore the implementation of the diabetes and hypertension guidelines at the primary care level, as well as to gain insight into how practitioners view the usability and practicality of the guidelines. Ten family health centres were randomly chosen from a list of all the family health centres (n = 136) located in Ulaanbaatar City. In each centre, a focus group discussion with nurses (n = 20) and individual interviews with practice doctors (n =10) and practice managers (n= 10) were conducted. Data was analysed using a thematic approach utilising the Theoretical Domains Framework.
Results: The majority of the study participants reported being aware of the guidelines and that they had incorporated them into their daily practice. They also reported having attended guideline training sessions which were focused on practice skill development. The majority of participants expressed satisfaction with the wide range of resources that had been supplied to them by the Mongolian Government to assist with the implementation of the guidelines. The resources, supplied from 2011 onwards, included screening devices, equipment for blood tests, medications and educational materials. Other enablers were the participants’ commitment and passion for guideline implementation and their belief in the simplicity and practicality of the guidelines. Primary care providers reported a number of challenges in implementing the guidelines, including frustration caused by increased workload and long waiting times, time constraints, difficulties with conflicting tasks and low patient health literacy.
Conclusions: This study provides evidence that comprehensive and rigorous dissemination and implementation strategies increase the likelihood of successful implementation of new guidelines in low resource primary care settings. It also offers some key lessons that might be carefully considered when other evidence-based clinical guidelines are to be put into effect in low resource settings and elsewhere.

Cleaning, resistant bacteria, and antibiotic prescribing in residential aged care facilities

Residents of residential aged care facilities (RACFs) are at risk of colonization and infection with multidrug-resistant bacteria, and antibiotic prescribing is often inappropriate and not based on culture-proven infection. We describe low levels of resident colonization and environmental contamination with resistant gram-negative bacteria in RACFs, but high levels of empirical antibiotic use not guided by microbiologic culture. This research highlights the importance of antimicrobial stewardship and environmental cleaning in aged care facilities.

Implementation of clinical guidelines on diabetes and hypertension in urban Mongolia: a qualitative study of primary care providers' perspectives and experiences

BACKGROUND: Hypertension and diabetes, key risk factors for cardiovascular disease, are significant health problems globally. As cardiovascular disease is one of the leading causes of mortality in Mongolia since 2000, clinical guidelines on arterial hypertension and diabetes were developed and implemented in 2011. This paper explores the barriers and enablers influencing the implementation of these guidelines in the primary care setting.

METHODS: A phenomenological qualitative study with semi-structured interviews was conducted to explore the implementation of the diabetes and hypertension guidelines at the primary care level, as well as to gain insight into how practitioners view the usability and practicality of the guidelines. Ten family health centres were randomly chosen from a list of all the family health centres (n = 136) located in Ulaanbaatar City. In each centre, a focus group discussion with nurses (n = 20) and individual interviews with practice doctors (n = 10) and practice managers (n = 10) were conducted. Data was analysed using a thematic approach utilising the Theoretical Domains Framework.

RESULTS: The majority of the study participants reported being aware of the guidelines and that they had incorporated them into their daily practice. They also reported having attended guideline training sessions which were focused on practice skill development. The majority of participants expressed satisfaction with the wide range of resources that had been supplied to them by the Mongolian Government to assist with the implementation of the guidelines. The resources, supplied from 2011 onwards, included screening devices, equipment for blood tests, medications and educational materials. Other enablers were the participants' commitment and passion for guideline implementation and their belief in the simplicity and practicality of the guidelines. Primary care providers reported a number of challenges in implementing the guidelines, including frustration caused by increased workload and long waiting times, time constraints, difficulties with conflicting tasks and low patient health literacy.

CONCLUSIONS: This study provides evidence that comprehensive and rigorous dissemination and implementation strategies increase the likelihood of successful implementation of new guidelines in low resource primary care settings. It also offers some key lessons that might be carefully considered when other evidence-based clinical guidelines are to be put into effect in low resource settings and elsewhere.